Project Summary Chronic back pain (daily pain for > 6 months) is one of the most prevalent and disabling complaints in VA healthcare. Effective treatment remains elusive. Most cases are not surgical candidates. Medical treatment relies upon non-steroidal anti-inflammatory drugs, opioids, and noradrenergic antidepressants. Among these the strongest evidence arguably supports use of noradrenergic antidepressants as analgesics, at lower concentrations than used to treat mood disorders, but only 50% of patients typically achieve satisfactory analgesia, and fewer show improved everyday function. A more integrated approach seems needed, particularly because evidence indicates that analgesia alone may not enhance everyday function. Research across a broad spectrum of psychiatric and medical disorders suggests that combining pharmacotherapy with cognitive behavioral therapy (CBT) improves outcomes. Leading authorities in chronic pain have called for studies that test multi-component versus single-modality therapies. Chronic back pain would seem to be the ideal target for a combination of an antidepressant and CBT, but no research addresses the efficacy of this integrated model for this population. We propose to test the utility of a personalized medicine approach (targeted low concentration antidepressant treatment with desipramine) plus brief CBT to provide analgesia, and improved function and life quality in chronic back pain. If successful this targeted intervention could be easily packaged and exported to primary care providers. The design is a 4-arm, 8-week, parallel groups, randomized clinical trial in men and women with chronic low back pain (N=200 total, 50 per arm) comparing 1) Antidepressant pharmacotherapy (desipramine, concentration15-65 ng/mL) + CBT; 2) Antidepressant pharmacotherapy alone; 3) CBT + Placebo Medication; and 4) Placebo Medication. One-month follow-up will test durability of effects. We propose a pragmatic clinical trial to test the utility of combined treatment rather than an explanatory clinical trial to establish therapeutic mechanisms. Therefore we will use placebo medication but not control for the non-specific effects of CBT (ie, therapist contact time) in this stage of research. Included will be men and women, aged 18-70, attending primary care clinics with chronic low back pain of at least moderate intensity (pain > 4 on 0-10 numeric pain rating scale) attributed to degenerative disc or joint disease. Excluded will be individuals with current major depression, substance use disorders, or co-morbid serious medical illness which could confound interpretation of outcomes. The primary analytic strategy will be intent-to-treat. We hypothesize that combination antidepressant + CBT will be superior to all other conditions. The primary efficacy assessment will be mean pain intensity (Descriptor Differential Scale) at exit. Secondary outcomes will be function (Roland and Morris Disability Questionnaire) and life quality (Short Form-36). Reassessment one month post-treatment will evaluate persistence of efficacy. Exploratory analyses will assess potential mediating and moderating variables of outcomes.